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784 PART 6: Neurologic Disorders

Therefore, patients requiring more than this amount in capsules should and permanent cerebral injury, as well as further systemic complica-
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usually receive divided doses. tions. Aggressive and rapid management is warranted, particularly when
Hypersensitivity is the major adverse effect of concern to the inten- considering that only two-thirds of patients in SE respond to the first
sivist. This may manifest itself solely as fever, but commonly includes treatment. 82
rash, eosinophilia, and elevated liver enzymes. Adverse reactions to The preferred agents used for first-line treatment of SE are benzodi-
phenytoin and other anticonvulsants have been reviewed elsewhere. azepines (especially lorazepam, diazepam, and midazolam), phenytoin,
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Over the recent years, levetiracetam has become increasingly popular as phenobarbital, levetiracetam, and valproate sodium. The Veterans
antiepileptic drug in the inpatient setting. Levetiracetam was originally Affairs Status Epilepticus Cooperative Study Group trial compared
approved in 1999 as add-on therapy for the treatment of partial-onset four regimens for the initial treatment of GCSE and demonstrated that
seizures in adults; by now, labeled use additionally includes myo- lorazepam was more efficacious than phenytoin, and easier to use than
clonic, and/or primary generalized tonic-clonic seizures. While the phenobarbital or phenytoin plus diazepam. Lorazepam has been our
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precise mechanism of action is unknown, inhibition of high-voltage- agent of first choice for terminating SE for many years and remains so
activated Ca channels and enhanced activity of potassium channels with support from this study.
2+
that maintain the resting membrane potential seem to be involved. The major advantage of lorazepam over diazepam is its longer dura-
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Levetiracetam can be administered as infusion or as oral solution or tion of action, thereby limiting seizure recurrence. Lorazepam has
tablet. Its half-life is 6 to 8 hours. The bioavailability of levetiracetam traditionally been given in 2-mg doses repeated at 5-minute intervals
is not dependent on food, it does not affect the protein binding of if seizures do not terminate. Since this is often an inadequate dose and
other drugs, and its distribution volume is close to that of total body valuable time passes before definitive treatment is instituted, we recom-
water. It is primarily metabolized by enzymatic hydrolysis, and renally mend instead a single IV dose of 0.1 mg/kg of lorazepam. If lorazepam
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excreted. Dose adjustment is needed in decreased renal function, and is not available, a single IV dose of 0.15 mg/kg of diazepam is an alterna-
approximately half of the drug is removed during hemodialysis, so that tive. However, another agent such as phenytoin or phenobarbital should
extra dosing is required after dialysis. 73,74 Furthermore, lack of hepatic be started immediately, as the duration of action of diazepam against
metabolism or interactions with other medications and few cardiac or SE is only about 20 minutes. In the event that IV access is unattainable,
peripheral venous effects are advantageous to levetiracetam, especially 0.2 mg/kg of midazolam administered IM will be rapidly and reliably
when compared with phenytoin. Its low incidence of serious adverse absorbed. The use of midazolam in refractory SE will be discussed
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reactions (as low as 1% for acute drug reactions ) and the lack of drug- below. All benzodiazepines carry a risk of hypotension and respiratory
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drug interactions make levetiracetam a safe medication in the elderly or depression. However, these are also sequelae of prolonged or inad-
multimorbid patient population. Patients treated with levetiracetam equately treated SE. The intensivist should be prepared to intubate or
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monotherapy in a neurological intensive care setting had lower compli- use vasopressors if necessary.
cation rates when compared to other antiepileptic drugs. When used RAMPART, a recently published double-blind, randomized trial
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for prophylaxis after neurological injury, patients treated with levetirace- comparing intramuscular midazolam with intravenous lorazepam in
tam had better outcomes at 3 months compared to patients treated with the prehospital treatment of SE, found that intramuscular midazolam
phenytoin. Levetiracetam is found at least as effective as phenytoin in was at least equally safe as intravenous lorazepam, particularly regard-
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the prevention of seizures after neurological injury or neurosurgery 76,79,80 ing the need for endotracheal intubation. Seizure termination was at
In the adult patient, effective doses of levetiracetam range from 500 to least as effective with intramuscular midazolam, the time-to-treatment
3000 mg/d. being significantly shorter for the intramuscular treatment likely playing
Phenobarbital remains a useful anticonvulsant for those intolerant a significant role. Phenytoin is an effective anti-SE agent; however, the
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to phenytoin or those who have persistent seizures after adequate phe- constraint on the rate of intravenous administration is of concern when
nytoin administration. The loading IV dose is 15 to 20 mg/kg, and the treating SE. Fosphenytoin may be a better drug for use in SE since it can
target serum concentration is 20 to 40 µg/mL. The serum concentration be loaded up to three times faster, although its 7-minute conversion half-
may be altered by hepatic and renal dysfunction. Furthermore, pheno- life means that the serum phenytoin level does not reach its target much
barbital can also induce P450-related metabolism, thereby affecting the faster. Phenytoin has a long duration of action when an adequate dose
metabolism of other drugs that undergo hepatic clearance. Since the is given (a 20-mg/kg dose produces a serum level above 20 mg/mL for
usual clearance half-life of phenobarbital is about 96 hours, maintenance 24 hours). Adding an additional 5 mg/kg if the initial load fails to stop
doses of this agent should be given once a day. A steady-state level takes SE may be useful. Intramuscular injection of fosphenytoin in SE patients
about 3 weeks to become established. Sedation is the major adverse may be supported by the known pharmacokinetics of this route, but it
effect; allergy to the drug occurs rarely. should not be considered to be acceptable therapy for SE and should be
Carbamazepine is rarely initiated in the ICU because it is not available reserved for only those rare circumstances in which IV access cannot
in parenteral form and absorption from the gastrointestinal tract is rela- be obtained.
tively slow. Carbamazepine has significant interactions with many drugs Levetiracetam is increasingly used as anti-SE agent, either as pri-
that are used in hospitalized patients, such as corticosteroids, theophyl- mary agent or as adjunct medication, due to its ease of use, the ease
line, warfarin, and cimetidine. Adjusting blood levels of carbamazepine of rapid intravenous infusion (15 minutes) and the tolerability in
in the setting of polypharmacy can be unpredictable. Carbamazepine critically ill patients due to very few serious adverse events and drug-drug
and the newer anticonvulsant oxcarbazepine can both cause hyponatre- interactions. Common dosing is a 500- to 2000-mg bolus followed by
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mia with chronic use, probably due to a combination of the syndrome 2000 to 3000 mg daily maintenance dose. The efficacy to abort SE has been
of inappropriate secretion of antidiuretic hormone (SIADH) and salt- found to be higher when loading with a bolus, and when initiated earlier
wasting nephropathy. during the course of SE. Several smaller series found intravenous leveti-
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■ STATUS EPILEPTICUS racetam highly effective in patients with SE refractory to benzodiazepines
or other initial therapy.
73,75
Status epilepticus is a medical emergency. While proper diagnosis of the Phenobarbital in the management of acute SE is not routinely rec-
cause is critical, the most important initial goal is to expeditiously stop ommended, except when phenytoin is contraindicated. However, the
the clinical and electrographic seizures. The likelihood of successfully Veterans Affairs study showed no difference in efficacy between loraz-
treating SE is inversely related to the duration of seizures; the longer epam and phenobarbital as first-line agents in SE, but phenobarbital
seizures last, the more difficult they are to terminate. Administration of took longer to administer. Furthermore, in the patients that did not
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antiepileptic drugs within 5 to 10 minutes has been shown essential to respond to lorazepam or phenytoin, the response rate to phenobarbital
limit the emergence of status epilepticus and related neuronal damage was only 2.1% (unpublished data). We therefore recommend pursuing a

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